Emergency (****); * (*): *-* This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2015 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com 59 Emergency (2015); 3 (2): 59-63 ORIGINAL RESEARCH A Randomized Clinical Trial of Intravenous and Intramuscular Ketamine for Pediatric Procedural Sedation and Analgesia Mohammad Gharavifard1, Behnaz Boroumand Reza Zadeh2, Hamid Zamani Moghadam2* 1. Department of Anesthesiology, Mashhad University of Medical Sciences, Iran. 2. Department of Emergency Medicine, Mashhad University of Medical Sciences, Iran. *Corresponding Author: Hamid Zamani Moghadam; Department of Emergency Medicine, Imam Reza Hospital, Mashhad, Iran. Tel: 985138525312; Email: zamanimh@mums.ac.ir Received: August 2014; Accepted: November 2014 Abstract Introduction: Ketamine is an agent broadly used for pediatric procedural sedation and analgesia in emergency departments. It has been found to be safe and with a low risk of complications. Choosing between intravenous (IV) and intramuscular (IM) injections is a matter of concern, so we did a comparison between the two methods in terms of their efficacy and rate of complications. Methods: This single-blind clinical trial recruited 240 children (age: three months to 15 years, weight > 5 kg), who underwent short and painful procedures at the emergency depart- ments. They were randomly allocated to two groups of 120 patients to receive either IV or IM ketamine with of 1.5 and 4 mg/kg doses, respectively. Indications for use, dose, side effects, and efficacy of the medications as well as duration of the procedure and time to recovery were compared between the two groups. Results: The mean age of the IV and IM groups were 6.5 ± 3.6 and 3.05 ± 2.6 years, respectively (p < 0.001). The onset of action of ketamine was 1.7 ± 1.1 minutes in the IV group and 8.6 ± 3.1 in the IM ones (p < 0.001). Patients of the IV and IM groups remained in optimal sedation for 20.6±12.0 and 37.2±11.8 minutes, respectively (P < 0.001) .Time until emergency department discharge was 65.3 ± 36.9 minutes in the IV group and 72.2 ± 14.5 in the IM group (P = 0.40) .Ketamine had excellent and moderate efficacy in 66.7% and 32.5% of the IV group and 70.0% and 25.0% in the IM group, respectively (p = 0.02). Totally, 60.0% of IV group patients and 40.0% of IM group experienced drug side effects (p = 0.21). Need for rescue dose was significantly higher in IV group (26.7% vs. 10.0%; p < 0.001). Finally, recovery was tranquil and comfortable in 88 patients (73.3%) of the IV group and 108 patients (90.0%) of the IM group (p = 0.06). Conclusion: We found that although the sedative and analgesic effects of IM and IV ketamine are not sig- nificantly different, duration of effect and onset of action are more desirable in the IV group for suturing, fracture reduction, and foreign body removal. Meanwhile, the IM method can lead to lesser need of rescue doses. Key words: Ketamine; analgesia; sedation; injections, intramuscular; infusions, intravenous Cite this article as: Gharavifard M, Boroumand Reza Zadeh B, Zamani Moghadam H. A randomized clinical trial of intravenous and intramuscular ketamine for pediatric procedural sedation and analgesia. Emergency. 2015;3(2):59-63. Introduction: etamine is an antagonist receptor of N-methyl-D- aspartate (NMDA) and phencyclidine derivate sedative agent broadly used for pediatric proce- dural sedation and analgesia (PSA) in emergency depart- ments (1-3). Rapid onset, relatively short-term effects, and excellent sedative and analgesic effects make it an appropriate choice for short and painful procedures. Nu- merous clinical trial studies have approved ketamine as a desirable and safe medication with low risk of emer- gence phenomena (4-10). Several studies in this field have compared two methods of intravenous (IV) and in- tramuscular (IM) administration based on time until hospital discharge and the incidence rate of side effects (6, 11-13). However, the superiority of either IV or IM application of the drug has been still under debate. Choosing the route of administration depends on availa- ble factors such as: emergency department facilities, pa- tient characteristics and comfort, and physician’s expe- rience and preference, drug’s complications and side ef- fects, and onset and duration of drug action (12-15). Since few studies were done among Iranian population in this regard, the present study was performed to iden- tify the preferable route for using ketamine by compar- ing the efficacy and side effects of the above-mentioned methods. K This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2015 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com Gharavifard et al 60 Methods: Study design and setting This single-blind clinical trial was conducted on three months to 15 years old children that weighted more than 5 kilograms, and required PSA for short and painful emergency procedures, who were presented to the emergency departments of Imam Reza and Hashemi- nejad Hospitals, Mashhad, Iran. Ethics committee of Mashhad University of Medical Sciences confirmed the study protocol and researchers were committed to the principles of the Helsinki declaration throughout the study period. Before any intervention, administered medication and its complications were thoroughly ex- plained for their parents and informed written consent was obtained from them. This trial is registered in Ira- nian registry of clinical trial (IRCT) under number IRCT2014071218454N1. Participants 240 children were recruited using convenience sam- pling. They were randomly allocated in two groups of 120 patients by using block randomization method. Sub- jects with a history of allergy to ketamine, severe cardi- ovascular diseases, thyroid disorders, head injury, cen- tral nervous system (CNS) disorders, glaucoma or acute globe injuries, history or evidence of psychosis, obstruc- tive sleep apnea, active pulmonary diseases such as up- per respiratory tract infection, tracheal stenosis or sur- gery, needed procedures associated with stimulation of posterior pharyngeal region, and those who were not willing to participate were excluded from the study. Intervention Sedation by ketamine was performed according to standard guidelines (14). Pulse oximetry and cardiac monitoring were constantly performed before, during, and after sedation. A nurse, blinded to the intervention, was present by the side of the patients during the whole procedure and not only recorded the routine nursing ob- servations and evaluations, but also any abnormal con- ditions until the patient recovered to his/her pre-proce- dure state. Venipuncture was performed for all patients to ensure blindness of the nurses and physicians. The first group of patients received IV ketamine (1.5 mg/kg, Infusion by 100 milliliter normal saline; maximum dose 200 mg), and the second took an IM dose (4 mg/kg; max- imum dose 200 mg). Patients with an open airway and adequate oxygen saturation, who were awake or could be easily awakened with minimal stimulation, able to drink liquids, and returned to the baseline level of con- sciousness were considered eligible for discharging from the emergency department. Outcomes The data regarding demographic characteristics, dura- tion of the procedure, the medicine’s onset and duration of action, efficacy, side effects, and time until emergency department discharge were gathered for all participants. At the end of the procedure, a specialist, who was blinded to the intervention, rated the efficacy of medi- cine in pain management and sedation as excellent (full sedation, immobility, and analgesia during the whole procedure), moderate (slight movements due to pain without interfering in the procedure), and poor (move- ments associated with pain that interfered in the proce- dure). The patients' status was followed for at least one hour in the recovery room and the incidence of any ad- verse effects was recorded. Children with restlessness or hallucinations were categorized as "recovery with agita- tion". In the absence of any side effects, the subjects were classified as "tranquil and comfortable". Statistical analysis The sample size calculation was performed based on de- tection of clinically significant differences in the inci- dence of vomiting. In a previous study, vomiting oc- curred in 18.3% and 35.4% of patients in IV and IM groups, respectively (11). With considering α = 0.05 and 80% power, 232 patients were needed to be enrolled. The collected data were entered to SPSS version 20.0 (SPSS Inc., Chicago, IL, USA) and described by using mean and standard deviation, graphs and tables. Varia- bles without normal distribution and ordinal ones were analyzed through Mann-Whitney U test. Chi-square test was also performed to compare qualitative variables be- tween the two groups. For assessment of any difference between IV and IM groups related to efficacy, side ef- fects, duration of the procedure, time to recovery and time to discharge we used generalized linear model ad- justed for baseline characteristics. P values less than 0.05 were statistically considered significant. Results: The mean age of the IV and IM groups were 6.5±3.6 and 3.05±2.6 years, respectively (p < 0.001). 80 (66.7%) and 60 (50.0%) cases were male in IV and IM groups, respectively (p = 0.009). The mean weight of the IV and Table 1: Demographic characteristics of children re- ceiving intravenous (IV) or intramuscular (IM) keta- mine Characteristics Group (%) p IV IM Age (years) 6.5 ± 3.6 3.05 ± 2.6 <0.001* Gender Male 80 (66.7) 60 (50.0) 0.009# Female 40 (33.3) 60 (50.0) Weight (kg) 2.3 ± 13 14.2 ± 8.6 <0.001* Procedure Suturing 81(67.5) 97 (81.0) 0.34# Fracture reduction 21(17.5) 11 (9.0) Foreign body removal 18 (15.0) 12 (10.0) Values are Number (%); *, Based on Mann-Whitney U test; #, Based on Chi-Squared test This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2015 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com 61 Emergency (2015); 3 (2): 59-63 IM groups were 22.3 ± 13.0 and 14.2 ± 8.6 kilograms, respectively (p < 0.001). Suturing, distal radius fracture reduction, and foreign body removal were performed for 178 (74.0%), 32 (13.5%), and 30 (12.5%) subjects, re- spectively (Table 1). The onset of ketamine action was 1.7 ± 1.1 (range: 1 - 5) minutes in the IV group and 8.6 ± 3.1 (range: 5 - 15) in the IM group (p < 0.001). Patients of the IV and IM groups remained in optimal sedation for 20.6 ± 12.0 (range: 6 - 45) and 37.2 ± 11.8 (range: 15 - 60) minutes, respectively (p < 0.001) .Time until emer- gency department discharge was 65.3 ± 36.9 minutes in the IV group and 72.2±14.5 minutes in the IM group (p = 0.40) (Figure 1) .Ketamine had excellent and moderate efficacy in 66.7% and 32.5% of the IV group and 70.0% and 25.0% in the IM group, respectively (p = 0.02) (Ta- ble 2). Totally, 60.0% of IV group patients and 40.0% of IM experienced drug side effects. After adjustment for age, gender, and weight there was no statistical signifi- cance (p = 0.21). Nausea and vomiting were observed in 40 (33.3%) patients of the IV group and 18 (15.0%) pa- tients of the IM ones (p = 0.21). Hallucinations were de- tected in 16 (13.1%) and 12 (10.0%) of the IV and IM groups, respectively (p = 0.30). IV and IM injections of ketamine resulted in agitation in 24 (20.0%) and 12 (10.0%) patients, respectively (p = 0.88). The frequency of respiratory depression was eight (6.8%) and 18 (15.0%) in the IV and IM groups, respectively (p = 0.29). Need to rescue dose was significantly higher in IV group (26.7% vs. 10.0%; p < 0.001) (Table 2). Finally, the re- covery was tranquil and comfortable in 88 patients (73.3%) of the IV group and 108 patients (90.0%) of the IM group (p = 0.06). Discussion: The results of the present study showed that although the sedative and analgesic effects of IM and IV ketamine were not significantly different, duration of effect and onset of action were more desirable in the IV group for suturing, fracture reduction, and foreign body removal. Meanwhile, the IM method led to fewer need to rescue doses. In general, because of no difference in side effects and recovery time between IV and IM methods, it was suggested that IV infusion of ketamine might be safer and more effective than IM injection for PSA. In 2006, Roback et al. compared the side effects, efficacy, and duration of sedation induced by IV and IM injection of ketamine in patients required orthopedic procedures. While respiratory complications in the two groups were similar (8.3% in the IV group vs. 4.0% in the IM group), the frequency of vomiting was higher in the IM group (26.3% vs. 11.9%). Moreover, the IM administration of ketamine was associated with significantly lower levels of pain and higher duration of sedation compared to the IV route. The researchers concluded that although IM in- jection of ketamine had better sedative properties com- pared to IV application, it was clearly accompanied by longer recovery and more vomiting (11). In spite of sim- ilar methodology, the findings of Roback et al. were in contrast with ours. The mean onset of action was 1.67 minutes in the IV group and 8.65 minutes in the IM group. In addition, mean time until emergency depart- ment discharge was 65.33 and 72.25 minutes in the above-mentioned groups, respectively. Consequently, the IV method was more favorable based on both speed of onset of action and time spent in the emergency de- partment. Since the efficacy difference between the two Table 2: Outcome of children receiving intravenous (IV) or intramuscular (IM) ketamine Factor Group Odds ratio 95% CI p* IV IM Efficacy Excellent 80 (66.7) 84 (70.0) Ref Ref Moderate 39 (32.5) 30 (25.0) 1.5 0.8 - 3.0 0.24 Poor 1 (0.8) 6 (5.0) 0.4 0.05 - 3.4 0.19 Need to rescue dose No 88 (73.3) 108 (90) Ref Ref Yes 32 (26.7) 12 (10.0) 5.8 2.5 -13.6 <0.001 Recovery Tranquil and comfortable 88 (73.3) 108 (90.0) Ref Ref Brief agitation 32 (26.7) 12 (10.0) 2.0 0.9 - 4.8 0.06 Side effects No side effects 48 (40.0) 72 (60.0) Ref Ref Nausea and vomiting 40 (33.3) 18 (15.0) 1.6 0.8 - 3.5 0.21 Hallucination 16 (33.3) 12 (10.0) 1.7 0.6 - 4.2 0.30 Agitation 24 (20.0) 12 (10.0) 1.1 0.4 - 2.7 0.88 Respiratory depression 8 (6.7) 18 (15.0) 0.5 0.1 - 1.8 0.29 Total 72 (60.0) 48 (40.0) 1.5 0.8 - 2.7 0.21 Values are Number (%); *, Based on generalized linear model adjusted for age, gender, and weight of patients; CI = confidence interval; Ref = reference category This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2015 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com Gharavifard et al 62 groups was not significant, no route of administration was favorable in terms of effectiveness (i.e. those causing optimal sedation and analgesia) .In evaluation of the side effects, we did not detect any significant difference be- tween groups. Unlike our findings, Roback et al. sug- gested this side effect to be more frequent following IM injections (11). In addition, in Ramaswamy et al. study side effects were seen in 35% of the IM group and 20% of the IV group. Moreover, time until discharge after the injection was 21 minutes shorter in the IV group. How- ever, time from the beginning of triage until discharging was similar in two groups. The time required for cathe- terization in the IV method was suggested to be respon- sible for such findings (13). Nevertheless, as we did not consider the time required for venipuncture, similar re- sults were obtained regarding time until discharge. In a review study in 2010, Deasy et al. reported that IV keta- mine injections were generally associated with fewer side effects and shorter duration of action compared to IM administration of the medicine. They concluded that when it is performed by a skilled person, the IV method could induce sedation more effectively than the IM method (16). Another review study by Green et al. in 2006 indicated shorter time until discharge and less ef- ficacy following the IV injections of ketamine. However, the researchers state that selecting the best route of ad- ministration depends on the physician’s decision based on the conditions and facilities of the hospital, particu- larly the emergency department and skillfulness of the staff (12). As the two groups in the current study had no significant difference in terms of efficacy, we recom- mend the same criteria for selecting the appropriate method. On the other hand, racial and environmental factors might have influenced on the effectiveness and side effects of the medicine, too. The present study contained some limitations. Because of difference in the method of administration, there was no possibility to blind the patient to the intervention, so the study was done as single-blind fashion. Furthermore, although the person who gathered the data was not in- formed about the injection method, he might be aware of the group that underwent therapy during clinical assess- ments. Thus, it could be possible to influence the blind- ness of the observer in some cases. To avoid such a prob- lem, the observer was trained not to ask anything from the patient regarding therapeutic interventions. Conclusion: It was found that although the sedative and analgesic ef- fects of IM and IV ketamine were not significantly differ- ent, duration of effect and onset of action were more de- sirable in the IV group for suturing, fracture reduction, and foreign body removal. Meanwhile, using the IM method can lead to lesser need for rescue doses. Acknowledgments: The authors appreciate the insightful cooperation of the staff of Emergency Department of Imam Reza Hospital, Mashhad, Iran. Conflict of interest: None Funding support: None Authors’ contributions: All authors passed four criteria for authorship contribu- tion based on recommendations of the International Committee of Medical Journal Editors. References: 1. Majidinejad S, Esmailian M, Emadi M. Comparison of Intravenous Ketamine with Morphine in Pain Relief of Long Bones Fractures: a Double-Blind Randomized Clinical Trial. Emergency. 2014;2(2):77-80. 2. Hosseini M, Karami Z, Janzadenh A, et al. 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